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Altered gene expression resulting from changes in the post-translational modification patterns of the histones and DNA is collectively termed epigenetics. Such changes are inherited albeit there are no alterations in the DNA sequence. Epigenetic regulation of gene expression is implemented by a wide repertoire of histone and DNA modifying enzymes including the acetyltransferases and deacetylases, the methyltransferases and kinases among others. Therefore, a regulation of these enzyme activities affords a tighter regulation of gene expression. Conversely, aberrant enzymatic activities lead to unregulated gene expression, resulting in several diseases such as RTS (loss of CBP HAT activity) and Spinal and Bulbar muscular atrophy (HATs and HMTases), apart from several forms of cancers, particularly myeloid leukemia (RAR-PML or RAR-PLZF fusion proteins resulting in the mistargeting of HDACs). Thus these enzymes have emerged as novel targets for the design of therapeutics. In this direction, several small molecule modulators (activators and inhibitors) of HATs, HDACs and HMTases are being reported in literature. This chapter introduces the different histone modifying enzymes involved in gene regulation, their connection to disease manifestation and focuses on the role of small molecule modulators in understanding enzyme function and also the design and the evolution of chromatin therapeutics [ABSTRACT FROM AUTHOR]

Human Immunodeficiency Virus type 1 (HIV-1) infection can now be treated effectively in many patients in the developed world, using combinations of antiretroviral therapeutics, called Highly Active Anti-Retroviral Therapy (HAART). However, despite prolonged treatment with HAART, the persistence of latently HIV-1-infected cellular reservoirs harboring transcriptionally silent but replication-competent proviruses represents the major hurdle to virus eradication. These latently infected cells are a permanent source for virus reactivation and lead to a rebound of the viral load after interruption of HAART. Therefore, a greater understanding of the molecular mechanisms regulating proviral latency and reactivation should lead to rational strategies aimed at purging these cellular reservoirs of HIV-1. This review summarizes our current knowledge and understanding of the elements involved in HIV-1 transcriptional reactivation: (1) the site of integration; (2) the transcription factor NF-κB, which is induced by proinflammatory cytokines (such as TNFα) and binds to two κB sites in the HIV-1 promoter region; (3) the specific remodeling of a single nucleosome (called nuc-1 and located immediately downstream of the HIV-1 transcription start site under latency conditions) upon activation of the HIV-1 promoter; (4) post-translational acetylation of histones and of non-histone proteins (following treatment with deacetylases inhibitors, which induce viral transcription and nuc-1 remodeling); and (5) the viral trans-activator Tat, which promotes transcription by mediating the recruitment to the HIV-1 promoter of histone-modifying enzymes and ATP-dependent chromatin remodeling complexes required for nucleosome disruption and transcriptional processivity. Finally, this review highlights experimental therapies aimed at administrating HIV-1 gene expression activators (such as HDAC inhibitors) combined with an effective HAART in order to reactivate and decrease/eliminate the pool of latently HIV-1-infected cellular reservoirs [ABSTRACT FROM AUTHOR]

Post-synthetic modification of histone proteins in chromatin architecture plays a central role in the epigenetic regulation of transcription. Histone acetylation and methylation are the two major modifications that function as a specific transcription regulator in response to various cellular signals. Albeit the mechanism of action of these modifications in transcription is not well understood, recent discovery of histone acetyltransferase (HAT) and methyltransferase (HMT) activities within transcriptional regulators has an important implication for histone modification to be a key player for the precise regulation of transcription processes. Here, we discuss recent advances made on histone acetylation and methylation as a fundamental process to modulate gene transcription, with a particular emphasis on their combinatorial effects in transcriptional control [ABSTRACT FROM AUTHOR]

First histone lysine methyltransferase (HLMTase) was discovered in 2000. Since then, there are reports of dozens of novel HLMTases in different eukaryotes including plant, fungus, insect, nematode and vertebrate. The enzymes and their specific histone-lysine modifications have enormous impacts on the regulation of chromatin structure and function. Furthermore, various histone methyl-lysine demethylases (HLDMases) have been identified recently. In this chapter, histone H3 lysine 9 specific methyltransferases will be discussed as model enzymes involved in the regulation of chromatin function [ABSTRACT FROM AUTHOR]

In eukaryotic cells, relaxed interphase chromatin undergoes pronounced changes resulting in formation of highly condensed mitotic chromosomes. Moreover, chromatin condensation is particularly evident during mitosis and apoptotic cell death, whereas chromatin relaxation is necessary for replication, repair, recombination and transcription. The post-translational modifications of histone tails such as reversible acetylation, phosphorylation and methylation play a critical role in dynamic condensation/relaxation that occurs during the cell cycle. Histone phosphorylation is believed to play a direct role in mitosis, cell death, repair, replication and recombination. However, definitive roles for this modification in these processes have not yet been elucidated. In this review, we discuss recent progress in studies of histone phosphorylation [ABSTRACT FROM AUTHOR]

The MYST family of histone acetyltransferases is highly conserved in eukaryotes and is responsible for the majority of acetylation events. These enzymes are exclusively found in multisubunit protein complexes, which structure is also very well conserved. Recent studies have shed light on the precise functions of these HAT complexes. They play critical roles in gene-specific transcription regulation, DNA damage response and repair, as well as DNA replication. Such roles in basic nuclear functions suggest that alteration of these MYST HAT complexes could lead to malfunctioning cells, leading to cell death, uncontrolled growth and/or disease. Indeed, many of these enzymes and their associated factors have been implicated in several forms of cancers. This chapter summarizes the current knowledge on MYST HAT complexes, their functions and link to human diseases. [ABSTRACT FROM AUTHOR]

During the development and maintenance of the central nervous system, neurons receive specific instructions to differentiate, survive or die, the correct choice being crucial for the maturation of a functional brain and to face pathological conditions. At the transcriptional level, chromatin remodeling enzymes participates in such processes. In this paper, we will see that disruption of the Histone acetyl transferase (HAT)/Deacetylase (HDAC) balance is often observed in different contexts of neurological disorders and more particularly during neuronal apoptosis. During the last 5 years, it has been evidenced that the chromatin acetylation status was greatly impaired in different neurodegenerative diseases, a common mechanism being the loss of function of a specific HAT: the CREB-binding protein (CBP). We will review the last attempts of the use of small molecules antagonizing HDAC activity (HDAC inhibitors) to restore proper levels of acetylation and enhance neuronal survival, both in in vitro and in vivo models of neurodegenerative diseases such as polyglutamine-related diseases and amyotrophic lateral sclerosis. Although this strategy lacks specificity towards CBP, certain of these molecules display promising therapeutic properties [ABSTRACT FROM AUTHOR]

One of the major mechanisms through which eukaryotic cells respond to developmental and environmental signals is by changing their gene expression patterns. This complex and tightly regulated process is largely regulated at the level of RNA polymerase II-mediated transcription. Within this process an important class of transcriptional regulators are the histone acetyltransferases (HATs), proteins that acetylate histones and non-histone substrates. While hyperacetylation of histones is generally associated with active genes, the effect of acetylation of nonhistone proteins varies between substrates resulting in for example alterations in (sub-nuclear) protein localization or protein stability. Given the central role of HATs in transcriptional regulation and other cellular processes, it may not be surprising that genetic alterations in the genes encoding HATs, resulting in aberrant forms of these regulatory proteins, have been linked with various human diseases, including congenital developmental disorders and various forms of cancer, including leukaemia. Here we will review mutations found in genes encoding human HATs and discuss the (putative) functional consequences on the function of these proteins. So far the lessons learned from naturally occurring mutations in humans have proven to be invaluable and recapitulating such genetic alterations in various experimental systems will extend our knowledge even further. This seems particularly relevant given the wide range of diseases in which acetyltransferases have been implicated and may help to open up new therapeutic avenues [ABSTRACT FROM AUTHOR]

The DNA in eukaryotic genome is compartmentalized into various domains by a series of loops tethered onto the base of nuclear matrix. Scaffold/ Matrix attachment regions (S/MAR) punctuate these attachment sites and govern the nuclear architecture by establishing chromatin boundaries. In this context, specific proteins that interact with and bind to MAR sequences called MAR binding proteins (MARBPs), are of paramount importance, as these sequences spool the proteins that regulate transcription, replication, repair and recombination. Recent evidences also suggest a role for these cis-acting elements in viral integration, replication and transcription, thereby affecting host immune system. Owing to the complex nature of these nucleotide sequences, less is known about the MARBPs that bind to and bring about diverse effects on chromatin architecture and gene function. Several MARBPs have been identified and characterized so far and the list is growing. The fact that most the MARBPs exist in a co-repressor/ co-activator complex and bring about gene regulation makes them quintessential for cellular processes. This participation in gene regulation means that any perturbation in the regulation and levels of MARBPs could lead to disease conditions, particularly those caused by abnormal cell proliferation, like cancer. In the present chapter, we discuss the role of MARs and MARBPs in eukaryotic gene regulation, recombination, transcription and viral integration by altering the local chromatin structure and their dysregulation in disease manifestation [ABSTRACT FROM AUTHOR]

Post-translational modifications of nonhistone proteins play a significant role in regulating the chromatin structure, dynamics and thereby gene regulation. Among the different posttranslational modifications, reversible acetylation of non-histone proteins has profound functional implications on wide range of cellular processes. The acetylation status of these proteins is regulated by several cellular and non-cellular factors like viruses, physiological stresses, DNA damaging agents and ROS. Mutations found in the acetylation sites of these proteins and aberrant acetylation are related to imbalances in different cellular pathways and various diseases. Several factor acetyltransferases and deacetylases are known to regulate the acetylation of the nonhistone proteins. Modulators of these enzymes derived from natural as well as synthetic sources can thus have important therapeutic implications. Designing strategies to specifically target the acetylation of these proteins can be used as a valuable tool for new generation drugs [ABSTRACT FROM AUTHOR]

Chemotherapy has been a major approach to treat cancer. Both constituents of chromatin, chromosomal DNA and the associated chromosomal histone proteins are the molecular targets of the anticancer drugs. Small DNA binding ligands, which inhibit enzymatic processes with DNA substrate, are well known in cancer chemotherapy. These drugs inhibit the polymerase and topoisomerase activity. With the advent in the knowledge of chromatin chemistry and biology, attempts have shifted from studies of the structural basis of the association of these drugs or small ligands (with the potential of drugs) with DNA to their association with chromatin and nucleosome. These drugs often inhibit the expression of specific genes leading to a series of biochemical events. An overview will be given about the latest understanding of the molecular basis of their action. We shall restrict to those drugs, synthetic or natural, whose prime cellular targets are so far known to be chromosomal DNA [ABSTRACT FROM AUTHOR]

Alteration of nuclear morphology is often used by pathologist as diagnostic marker for malignancies like cancer. In particular, the staining of cells by the silver staining methods (AgNOR) has been proved to be an important tool for predicting the clinical outcome of some cancer diseases. Two major argyrophilic proteins responsible for the strong staining of cells in interphase are the nucleophosmin (B23) and the nucleolin (C23) nucleolar proteins. Interestingly these two proteins have been described as chromatin associated proteins with histone chaperone activities and also as proteins able to regulate chromatin transcription. Nucleolin seems to be over-expressed in highly proliferative cells and is involved in many aspect of gene expression: chromatin remodeling, DNA recombination and replication, RNA transcription by RNA polymerase I and II, rRNA processing, mRNA stabilisation, cytokinesis and apoptosis. Interestingly, nucleolin is also found on the cell surface in a wide range of cancer cells, a property which is being used as a marker for the diagnosis of cancer and for the development of anti-cancer drugs to inhibit proliferation of cancer cells. In addition to its implication in cancer, nucleolin has been described not only as a marker or as a protein being involved in many diseases like viral infections, autoimmune diseases, Alzheimer's disease pathology but also in drug resistance. In this review we will focus on the chromatin associated functions of nucleolin and discuss the functions of nucleolin or its use as diagnostic marker and as a target for therapy [ABSTRACT FROM AUTHOR]

Histone chaperones are the histone interacting factors that stimulate histone transfer reaction without being a part of the final product. They are involved in the histone storage, histone translocation to the nucleus, and histone exchange and histone deposition onto the DNA for replication dependent chromatin assembly. Interestingly, they have also been demonstrated to possess the histone removal activity. While the involvement of the histone chaperones in chromatin transcription is undisputed, the question of their local versus global involvement is under scrutiny. This review enumerates the role played by various histone chaperones in the establishment of chromatin structure and regulation of chromatin transcription. The role of histone chaperones in disease manifestation is not very clear, preliminary results with few histone chaperones suggest that expression and function of these factors dramatically alters in carcinogenesis. This review will also focus on the possible role of histone chaperones in cancer diagnosis and progression [ABSTRACT FROM AUTHOR]

In contrast to canonical histones, which are assembled into nucleosomes during DNA replication, histone variants can be incorporated into specific regions of the genome throughout the cell cycle. Recent findings suggest that histone variants associate with factors mediating their deposition into specialized chromatin domains. The mechanisms of their targeted deposition, their turnover, and their posttranslational modification are not yet fully understood. Emerging evidence indicates that histone variants and associated factors are essential for the epigenetic control of gene expression and other cellular responses. Thus, histone variants and complexes involved in their exchange are likely to play major roles in controlling chromosomal architecture, and their deregulation is expected to be linked to cancers, infertility, mental disorders, ageing, and degenerative diseases [ABSTRACT FROM AUTHOR]

Histone variant are non-allelic forms of the conventional histones. They are expressed at very low levels compared to their conventional counterparts. All the conventional histones, except H4, have histone variants. Together with histone modifications and chromatin remodeling machines, the incorporation of histone variants into the nucleosome is one of the main strategies that the cell uses to regulate transcription, repair, chromosome assembly and segregation. The exact role of the histone variants in these processes is far from clear, but the emerging picture is that the presence of histone variants confers novel structural and functional properties of the nucleosome which affect the chromatin dynamics. In this article we will discuss the functional significance of histone variants on chromatin function and its link to disease manifestation [ABSTRACT FROM AUTHOR]

Poly(ADP-Ribose) Polymerase-1 (PARP-1) is the prototypical and most abundantly expressed member of a family of PARPs that catalyze the polymerization of ADP-ribose (ADPR) units from donor NAD+ molecules on target proteins. PARP-1 plays roles in a variety of genomic processes, including the regulation of chromatin structure and transcription in response to specific cellular signals. PARP-1 also plays important roles in many stress-induced disease states. In this chapter, we review the molecular and cellular aspects of PARP-1's chromatin-modulating activities, as well as the impact that these chromatin-modulating activities have on the regulation of gene expression. In addition, we highlight the potential therapeutic use of drugs that target PARP-1's enzymatic activity for the treatment of human diseases [ABSTRACT FROM AUTHOR]

Alterations of chromatin structure play an important role in gene regulation. One way of doing so involves ATP-dependent chromatin remodelling enzymes that act as molecular machines coupling ATP-hydrolysis to structural changes of the nucleosome. Several recent studies shed important insights into the mechanism of these factors and indicate that they couple DNA translocation within the nucleosome to DNA loop propagation through the nucleosome. This reaction causes the movement of a nucleosome with respect to a given DNA sequence and also drives its disassembly. It is becoming clear that the biology of these factors is very complex considering the plethora of known ATP-dependent nucleosome remodelling factors and their many, in part overlapping functions and varied ways of regulation and targeting. Finally, nucleosome remodelling may only be one aspect of the function of these enzymes, because they may impart or regulate higher order levels of chromatin organization. The importance of these enzymes for normal growth and development is illustrated by disorders and neoplasias linked to mutations of those factors or their misregulation. Given that these enzymes have such profound roles in gene expression and cell proliferation, they may constitute important drug targets for clinical applications in the future [ABSTRACT FROM AUTHOR]